Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia-induced sepsis is a common cause of morbidity in the intensive care unit. Although pneumonia is initiated in the lungs, extrapulmonary manifestations occur commonly. In light of the key role the intestine plays in the pathophysiology of sepsis, we sought to determine whether MRSA pneumonia induces intestinal injury. ⋯ To determine if these findings were organism-specific, similar experiments were performed in mice subjected to Pseudomonas aeruginosa pneumonia. Pseudomonas aeruginosa induced gut apoptosis, but unlike MRSA, this was associated with increased Bcl-2 and TNF-R1 and decreased Fas. Methicillin-resistant S. aureus pneumonia thus induces organism-specific changes in intestinal apoptosis via changes in both the mitochondrial and receptor-mediated pathways, although the former may be more functionally significant.
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Glucocorticoids remain a recommended therapy in advanced septic shock despite the often unpredictable response, and our understanding of the mechanisms regulating the steroid and stress response remains limited. Since the initial sequencing of the human glucocorticoid receptor α and β gene (hGRα and hGRβ), only three additional splice variants have been identified--all of which have been postulated to contribute to steroid resistance. During a survey of 97 healthy humans' blood, we identified two novel hGR splice isoforms (hGR-S1 and hGR-S1(-349A) retaining intron H between exons 8 and 9. ⋯ Removal of the 3' untranslated region (3'UTR) of the hGR-S1(-349A) mRNA sequence resulted in a loss of the augmented response. The isoform hGR-S1(-349A) augments the response to steroids, and this significant response appears to be critically regulated by the 3'UTR. The identification and evaluation of these unique hGR isoforms helps further the understanding of the complex genetic regulation of the stress and steroid response.
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More than 50% of severely injured patients have chest trauma. Second insults frequently result in acute lung injury (ALI), with sepsis being the main underlying condition. We aimed to develop a standardized, reproducible, and clinically relevant double-hit mouse model of ALI induced by chest trauma and polymicrobial sepsis and to investigate the pathophysiologic role of activated neutrophils. ⋯ Neutrophil depletion significantly diminished lung interleukin 1β and interleukin 6 concentrations and reduced the degree of septic ALI. Here we have established a novel and highly reproducible mouse model of chest trauma-induced septic ALI characterizing a clinical relevant double-hit scenario. In particular, the depletion of neutrophils substantially mitigated the extent of lung injury, indicating a pathomechanistic role for neutrophils in chest trauma-induced septic ALI.
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Comparative Study
A comparison of the time from sepsis to inception of continuous renal replacement therapy versus RIFLE criteria in patients with septic acute kidney injury.
We hypothesized that the time from sepsis to inception of continuous renal replacement therapy (CRRT) can be used to predict survival rates in patients with septic acute kidney injury (AKI). The survival predictability of CRRT inception time was compared with that of RIFLE criteria, which were previously used in clinical practice. We retrospectively analyzed outcomes in 55 patients with septic AKI admitted to the medical intensive care unit at Asan Medical Center (Seoul, Korea) between April 2009 and October 2010. ⋯ Ventilator-free day at day 28 was longer in the early group than that in the late group (7.5 vs. 0 d; P = 0.033). After adjustment for covariates, we found that the late group (hazard ratio, 3.106; 95% confidence interval, 1.066-9.047) and Sequential Organ Failure Assessment at sepsis (hazard ratio, 1.410; 95% confidence interval, 1.108-1.796) were independent factors associated with 28-day mortality. This study suggests that the time interval from sepsis to CRRT inception may be a more useful predictor of 28-day mortality than RIFLE criteria in patients with septic AKI.
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Activation of the complement system has been associated with tissue injury after hemorrhage and resuscitation in animals. We investigated whether administration of recombinant human C1-esterase inhibitor (rhC1-INH), a regulator of complement and contact activation systems, reduces tissue damage and cytokine release and improves metabolic acidosis in a porcine model of hemorrhagic shock. Male Yorkshire swine were assigned to experimental groups and subjected to controlled, isobaric hemorrhage to a target mean arterial pressure of 35 mmHg. ⋯ The tissue-protective effects of rhC1-INH appear to be related to its ability to reduce tissue complement activation and deposition. Recombinant human C1-INH decreased tissue complement activation and deposition in hemorrhaged animals, improved metabolic acidosis, reduced circulating tumor necrosis factor α, and attenuated tissue damage in this model. The observed beneficial effects of rhC1-INH treatment on tissue injury 20 min into severe hypotension present an attractive model of low-volume resuscitation, particularly in situations with a restrictive medical logistical footprint.